16α-methylation process

ABSTRACT

Disclosed is a process for the production of a Δ 17 (20) -steroid of the formula ##STR1## which comprises starting with a 16-unsaturated corticoid of the formula ##STR2## and contacting the 16-unsaturated corticoid (I) with a methylating agent in the presence of a copper catalyst and a silylating agent.

The present patent application (3915.P CN) is a continuation of the U.S.national application of PCT application PCT/US87/01,153, filed 5-21-87(3915.P), which was a continuation-in-part application of U.S. patentapplication Ser. No. 870,364, filed 6-4-86 (3915.1.1, now abandoned),which was a continuation-in-part application of U.S. patent applicationSer. No. 724,380, filed 4-18-85 (3915.1, now U.S. Pat. No. 4,704,455),which was a continuation-in-part application of U.S. patent applicationSer. No. 618,986, filed 6-11-84 (3915, now abandoned).

BACKGROUND OF THE INVENTION

Corticoids with a 16α-methyl group are known to be usefulanti-inflammatory agents. These include dexamethasone(9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione),flumethasone60α,9α-difluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione)and paramethasone(6α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione).

The 16-unsaturated corticoid (I) starting materials are known, see, U.S.Pat. Nos. 2,864,834, 3,210,341, 3,839,369, 4,031,080 and 4,277,409.

The transformation of 16-unsaturated pregnanes to 16α-methyl pregnanesby use of a Grignard reagent is known. The conjugate addition of a16α-methyl group to a 16-unsaturated-20-keto steroid by means of amethyl Grignard reagent in the presence of a copper salt catalyst iswell known. see Organic Reactions in Steroid Chemistry, Vol II, J. Friedand J. A. Edwards, Van Nostrand Reinhold Co., NY, 1972, p 75. Theproduct of such a reaction is the 16α-methyl-Δ¹⁷ (20) -20-enolate, whichaccording to Fried may be trapped as the 20-acetate, see p 76. While theaddition can go 1,2 or 1,4 with a ratio of about 1:1, the addition ofcuprous chloride gave exclusively 1,4-addition in yields of greater than90%.

U.S. Pat. No. 3,231,568 (JULIAN) discloses the transformation of a16-unsaturated progesterone to the corresponding17α-hydroxy-16α-methylprogesterone. However, JULIAN's pregnane did nothave a second α/β-unsaturated ketone in the form of a Δ⁴ -3-ketone orΔ¹,4 -3-ketone as the steroid A-ring was 3,5-cyclo. In addition. JULIANdisclosed a progesterone having no C₂₁ functionality while the processof the present invention uses a 21-acylate which is sensitive to theGrignard reaction and is hydrolyzable. The C-ring of JULIAN contained nosubstitution and therefore was not sensitive to the oxidation reactionconditions. A further distinction is that JULIAN traps with acetate andthe enol acetate of JULIAN is not reactive to the mild peracidconditions of the present process and hence would not form the desired17,20-epoxide (III).

U.S. Pat. No 4,031,080 (PALLADINO) uses copper for the conjugateaddition reaction but produces an enol acetate which as JULIAN wouldteach would be unreactive to the mild and selective peracid reactionconditions of this invention producing the desired 17,20-epoxide (III).PALLADINO produces 17α-bromo-16α-methyl corticoid not a17α-hydroxy-16α-methyl corticoid.

U.S. Pat. No. 4,277,409 (WARNANT) transforms a 16-unsaturated-21-acetateto a 16α-methyl-21-acetate, without introducing the necessary17α-hydroxyl group while the process of the present invention introducesthe desired 17α-hydroxyl group.

Great Britain Patent 2,001,990 discloses a process to transform a16-unsaturated corticoid (I) to the corresponding 16α-methyl corticoid(V) by methylating the 16-unsaturated corticoid with copper catalyzedmethyl grignard to produce the 16α-methyl-Δ¹⁷(20) -20-(magnesiumbromide)enolate, followed by conversion by oxygenation to a17α-hydro-peroxide which is reduced to the corresponding16α-methyl-17α-21-dihydroxy-20-one 21-acetate. The process of thepresent invention does not produce a 17α-hydroperoxide, but ratherutilizes a 17α-20-epoxide (III) intermediate.

U.S. Pat. No. 3,072,686 (WETTSTEIN) discloses the transformation of a16-unsaturated progesterone to a 17α-hydroxy-16α-methylprogesterone byreacting the 16-unsaturated progesterone with a Grignard reagent andcuprous chloride. WETTSTEIN produces a Δ¹⁷(20) -20-enol acetate which isnot reactive to the mild and selective peracid conditions of the presentprocess and hence would not form the desired 17,20-epoxide (III).

Both J. Am. Chem. Soc. 80, 3160 (1958) and J. Am. Chem. Soc. 80, 4428(1958) report the transformation of a 16-unsaturated progesterone to a16α-methylprogesterone by use of a Grignard reagent followed by peracidoxidation to introduce the 17α-hydroxy group producing a17α-hydroxy-16α-methylprogesterone. The17α-hydroxy-16α-methylprogesterone is brominated and acylated to formthe 21-acetoxy-17α-hydroxy-16α-methyl steroid.

E. J. Corey in Tetrahedron Letters 26, 6019 (1985), [COREY], disclosesthe reaction of a methylating agent (lithium dimethylcuperate) with anα,β-enone in the presence of a trapping agent (chlorotrimethylsilane).The significant difference between COREY and the present patentapplication is that COREY used preformed alkyl-cuperate where as thepresent invention generates the cuperate methylating agent in situ.Likewise, A. Alexakis in Tetrahedron Letters 27, 1047 (1986),[ALEXAKIS], discloses the reaction of lithium alkyl-cuperate withunsaturated esters in the presence of trimethylsilyl chloride anddemonstrates an increased yield of the alkylated product. However, againALEXAKIS like COREY used preformed cuperate whereas the presentinvention generates the cuperate methylating agent in situ.

U.S. Pat. No. 3,700,660 discloses a process of converting a20-acyloxy-17,20-epoxy steroid to a 17α-acyloxy-20-keto steroid by useof a strong acid. U.S. Pat. No. 3,700,660 (HEMPEL) uses 20-acetate wherethe process of the present invention uses 20-silyl. The significance ofthis is that the Δ¹⁷(20) -20-enol silane (II) of the present inventionis much more reactive than the corresponding 20-acylate of HEMPEL whichpermits epoxidation of the Δ¹⁷(20) double bond in steroids having otherdouble bonds such as Δ⁴ -3-keto, Δ¹,4 -3-keto, Δ⁹(11) -etc. whereas the20-acylate of HEMPEL is limited to a non-functionalized steroid.

U.S. Pat. Nos. 3,513,163 and 4,036,831 disclose C₂₁ and C₁₁trimethyl-siloxy ethers respectively. Δ¹⁷(20) -20-O-substituted steroidsare known where the substituent is an acyl group or a Grignardsubstituent (--Mg-X), see U.S. Pat. Nos. 3,072,686, 3,231,568 and4,031,080. This Mg-X substituted compound while disclosed is notisolatable.

17α,20-Epoxy-16α-methyl-20-O-substituted steroids are disclosed in U.S.Pat. No. 3,876,633 where the 20-O-substituent is an acyl group, seeclaim 9.

Selective epoxidation of the Δ⁹(11) double bond over the Δ¹⁶ double bondin a Δ⁹(11),16 -diene is set forth in U.S. Pat. No. 3,876,633. U.S. Pat.No. 3,876,633 discloses 9β,11β-epoxy-Δ¹⁶ -steroids where the A-ring isreduced.9β,11β-epoxy-6α-fluoro-21-hydroxypregna-1,4,16-triene-3,20-dione21-acetate is disclosed in U.S. Pat. No. 3,210,341, Example 9(b).

U.S. Pat. No. 4,036,831 discloses a process of protecting the11β-hydroxyl group of a steroid, during subsequent reactions, withtrimethylsilyl and the subsequent removal of the trimethvlsilyl group byhydrolysis with 40-60% aqueous hydrogen fluoride.

SUMMARY OF THE INVENTION

Disclosed are the Δ¹⁷(20) -steroid (II A-C), a 17α,20-epoxide (III A-C)and the 17α-silyl ether (IV A-C).

Further disclosed is a process for the preparation of a Δ¹⁷(20) -steroid(II A-C) which comprises starting with a 16-unsaturated corticoid (IA-C) and (1) contacting the 16-unsaturated corticoid (I A-C) with amethylating agent in the presence of a copper catalyst and (2)contacting the product of step (1) with a silylating agent.

Also disclosed is a process for the preparation of a 17α,20-epoxide (IIIA-C) which comprises starting with a Δ¹⁷(20) -steroid (II A-C) andcontacting it with a peracid.

Additionally disclosed is a process for the preparation of aΔ¹⁷(20)-steroid (II A-C) which comprises starting with a 16-unsaturatedcorticoid (I A-C) and contacting the 16-unsaturated corticoid (I A-C)with a methylating agent in the presence of a copper catalyst and asilylating agent.

DETAILED DESCRIPTION OF THE INVENTION

The 16-unsaturated corticoid (I A-C) starting materials are well knownto those skilled in the art or can be readily prepared from knownsteroids by methods well known to those skilled in the art. see, forexample, U.S. Pat. Nos. 2,773,080, 2,864,834, 3,210,341, 3,441,559.3,461,144, 3,493,563, 3,839,369, 4,031,080, and 4,277,409.

The C₃ functionality of the Δ⁴ -3-keto (A), Δ¹,4 -3-keto (B) and3β-hydroxy-Δ⁵ - (C) steroid does not have to be protected for theprocesses of the present invention. The 3β-hydroxy-Δ⁵ - (C) steroid canhave its C₃ -hydroxyl group (Ca) protected as the silyl ether (Cb),ether (Cc) or ester (Cd), see Chart C. The free hydroxyl group (Ca) canbe protected as the ether (Cc) or ester (Cd) as is well known to thoseskilled in the art. See Protective Groups in Organic Synthesis, TheodoraW Greene, Wiley & Sons. New York 1981. The ethers (Cc) are prepared bymethods well known to those skilled in the art, see Steroid Reactions,Edited by Carl Djerassi, Holden-Day, San Francisco 1967, p 76.82. If thefree 3β-hydroxyl group (Ca) is not protected as the ether (Cc) or ester(Cd) during the silation reaction, the free hydroxy group will besilated to form the silyl ether (Cb). During the silylation reaction, ifthe 3β-hydroxyl group is free and will be silylated, one additionalequivalent of Grignard and silylating agent will be consumed. The C₃protected forms of the 3β-hydroxy steroids (C) are considered equivalentto the non-protected or free form (C) respectively since the C₃protecting groups are readily removable to convert the C₃ protectedforms (Cb, Cc and Cd) to (A and C). The protecting group remains onuntil the hydrolysis (acid or base) of the 17α,20-epoxide. If acidhydrolysis is utilized and the C₃ protecting group is acid labile (Cband Cc) it will be removed. Likewise if base hydrolysis is utilized andthe C₃ protecting group is base.sensitive (Cd) it will be removed. Ifthe C₃ protecting group is not sensitive to the hydrolysis agent. the C₃protected steroid will have to be treated with the appropriate agent toremove the C₃ protecting group.

It is preferred that the 16-unsaturated corticoid (I A-C) be a Δ⁴-3-keto (A) or a Δ¹,4 -3-keto (B) corticoid, more preferably a Δ¹,4 -3-keto (B) corticoid. It is preferred that the 16-unsaturated corticoidhave the C-ring Δ⁹(11) or 9β,11β-epoxy. It is more preferred that theC-ring be 9β,11β-epoxy. It is preferred that R₆ be a hydrogen orfluorine atom. more preferred that R₆ be a hydrogen atom.

While it is preferred that the C-ring is Δ⁹(11) or 9β,11β-epoxy, theC-ring can be converted to the desired 9α-fluoro-11β-hydroxyfunctionality prior to the Grignard addition of the methyl group to theΔ¹⁶ double bond. If this is done. the 11β-hydroxy group should beprotected as is well known to those skilled in the art, see for example.U.S. Pat. No. 4,036,831 where the protecting group is trimethylsilyl.Following the formation of the desired 16α-methyl corticoid, the(trimethylsilyl) protecting group is removed as is well known to thoseskilled in the art, see for example, U.S. Pat. No. 4,036 831.

The conjugate addition of a methylating agent, such as methyl Grignard,to a 16-unsaturated steroid to give the corresponding 16α-methyl steroidis well known, see Organic Reactions in Steroid Chemistry, Vol. II, J.Fried and J. A. Edwards, p 75 and U.S. Pat. No. 3,072,686.

The 16-unsaturated corticoid (I) is reacted with a methylating agenteither followed by or in the presence of a trapping (silating) agent togive the enol silane Δ¹⁷(20) -steroid (II). It is preferred that the16-unsaturated corticoid (I) is reacted with a methylating agent in thepresence of the trapping agent rather than adding the trapping agentafter the 16-unsaturated corticoid (I) is reacted with the methylatingagent. The methylating agent is selected from the group consisting ofCH₃ Cu. (CH₃)₂ CuM or CH₃ MgQ and a catalytic amount of a copper(cupric) salt. The preferred methylating agent is methyl Grignard,preferably methyl magnesium chloride. The copper salt can be a cuproussalt such as cuprous chloride, bromide, iodide or cyanide or a cupricsalt such as cupric chloride, cupric acetate, cupric propionate orcomplexes thereof. Examples of copper complexes include, cuprous bromidedimethylsulfide cuprous chloride tris-n-butylphosphine and cuprousacetylacetonate. The nature of the copper complex is not critical.Hundreds (or thousands) of copper complexes are known which areconsidered equivalent to those set forth above. Preferred is cupricacetate or propionate, more preferred is cupric propionate. Additionalcatalysts which are considered equivalent to those disclosed above arewell known to those skilled in the art, see, for example, Alfa Catalog,1983-1984, Morton Thiokol, Inc., Alpha Products, PO Box 299, 152 AndoverStreet, Danvers, Mass. 01923. Depending on the physical facilities, itmay be preferred that the cupric propionate be predissolved. Solventssuitable for the methylation reaction include those selected from thegroup consisting of THF, t-butylmethyl ether or dimethoxyethane. Thereaction is performed in a range of from about -50° to about 20°,preferably at about -20°. When TLC indicates that no starting materialis left (indicating the probable formation of an enolate intermediate),the silating agent is added and the resulting product is the Δ¹⁷(20)steroid (II). After the silylating agent is added the reactiontemperature is kept in the range of about -25° to about 25°, preferablyabout 0°. It is preferable to filter the Grignard reaction mixture toprevent residual copper from entering the peracid reaction.

In the present invention the enolate intermediate is trapped with atrapping (silylating) agent which gives the Δ¹⁷(20)-20-(substitutedsilyl) product. Operable silylating agents include (R₂₀)₃ -Si-E,bistrimethylsilylacetamide. It is preferred that the silating agent beof the formula (R₂₀)₃ -Si-E, more preferably trimethylsilyl chloride.Additional silylating agents considered equivalent to those disclosedabove are well known to those skilled in the art, see, for exampleSilicon Compounds, Petrarch Systems, Inc.. Bartram Rd. Bristol, Pa.19007. While the silylating agent can be present while the enolate isformed or added after the enolate is formed. it is preferred that thesilylating agent be present when the enolate is formed. The trapping ofthe enolate intermediate to produce the Δ¹⁷(20) -20-(acetate) is known.see U.S. Pat. No. 4,031,080 and Organic Reactions in Steroid Chemistry,Vol. II, supra, p 76. These enol acylates are too unreactive to reactselectively over

A,B,C-ring functionality such as Δ⁹(11). However surprisingly andunexpectedly the Δ¹⁷(20) -20-(substituted silyl) derivative (II) issufficiently reactive to react with electrophiles without affecting mostof the other functionality in the A,B,C-rings.

The Δ¹⁷(20) -steroid (II) can be isolated if desired by means well knownto those skilled in the art, see for example. Examples 1 and 8. However,since the desired product is the 16α-methyl corticoid (V), it is notnecessary and preferable not to isolate the Δ¹⁷(20) -steroid (II) butrather to continue the reaction, see Examples 3-5, 11 and 12.

The Δ¹⁷(20) -steroid (II) is reacted with a peracid to produce the17α,20-epoxide (III). While most peracids are operable, preferredperacids includs m-chloroperbenzoic, perbenzoic, peracetic. Theperacid-reaction conditions are well known to those skilled in the art.The peracid reaction does not significantly affect the Δ¹, Δ⁴, or Δ⁹(11)functionalities in the remainder of the molecule, see Example 2. Thesolvent used during the methylation reaction producing the Δ¹⁷(20)steroid (II) is removed and replaced by a non-polar solvent such astoluene, methylene chloride. ethyl acetate or t-butyl methyl ether. Theinorganic salts remaining after the methylation reaction are removed byextraction. The peracid oxidation is performed in the temperature rangeof about -30° to 25°, preferably about -20°. When the reaction iscomplete, the excess peracid is destroyed by addition of an agent suchas powdered sodium thiosulfate or sodium bisulfite. The 17α,20-epoxide(III) can be isolated if desired by means well known to those skilled inthe art. However, since the desired product is the 16α-methyl corticoid(V), it is not necessary and preferable not to isolate the17α,20-epoxide (III) but rather to continue the reaction in situ.

The 17α,20-epoxide (III) is transformed to the corresponding 16α-methylcorticoid (V) by acid or base hydrolysis. If base is used the 16α-methylcorticoid will be obtained as the 21-hydroxy compound (R₂₁ is a hydrogenatom). If acid is used the 16α-methyl corticoid will be the 21-ester(R₂₁ is --CO--R₂₁ '). Suitable base hydrolyzing agents includehydroxide, carbonate, bicarbonate, alkoxide in alcohol at lowtemperature etc. It is preferred that the hydrolyzing agent be an acid.Suitable acids include mineral acids and other sufficiently strong acidssuch as p-TSA, sulfuric hydrochloric citric or acetic. The acidhydrolysis is sufficiently fast that the reaction is complete in about1/2 hour at 20°-25°.

The 16α-methyl corticoids (V) are adrenocorticoid agents withglucocorticoid activity and are useful primarily for theiranti-inflammatory effects as is well known to those skilled in the art.These include dexamethasone, flumethasone and paramethasone. One of thebest known 16α-methyl corticoids is dexamethasone. see U.S. Pat. No.3,375,261 and U.S. Pat. No. Re. 28,369 as well as the Physicians DeskReference 1983, 37th Edition, p 1270-1283.

If the C-ring of the 16α-methyl corticoid (V) is Δ⁹(11) or 9β,11β-epoxy,it is readily convertible to the pharmacologically active9α-fluoro-11β-hydroxy C-ring by means well known to those skilled in theart.

DEFINITIONS

The definitions and explanations below are for the terms as usedthroughout the entire patent application including both thespecification and the claims.

All temperatures are in degrees Centigrade.

TLC refers to thin.layer chromatography.

THF refers to tetrahydrofuran.

TMS refers to trimethylsilyl.

THP refers to tetrahydropyranyl

EEE refers to (1-ethoxy) ethyl ether [--O--CH(CH₃)OCH₂ CH₃ ].

p-TSA refers to p-toluenesulfonic acid monohydrate.

When solvent pairs are used. the ratio of solvents used arevolume/volume (v/v).

DMSO refers to dimethylsulfoxide.

UV refers to ultraviolet spectroscopy.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from tetramethylsilane.

[α]D²⁵ refers to the angle of rotation of plane polarized light(specific optical rotation) at 25° with the sodium D line (5893A).

Dexamethasone refers to9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione.

Paramethasone refers to6α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione.

Flumethasone refers to6α,9α-difluoro-11β,17α,21-trihydroxy-16°-methylpregna-1,4-diene-3,20-dione.

R₃ is alkyl of 1 thru 3 carbon atoms, a TMS, THP, or EEE group.

R₃ ' is alkyl of 1 thru 5 carbon atoms or phenyl.

R₆ is a hydrogen or fluorine atom or methyl group.

R₉ is nothing, a hydrogen, fluorine or oxygen atom which makes theC-ring

(a) Δ⁹(11) when R₉ is nothing and

(b) 9β,11β-epoxide when R₉ and R₁₁ taken together are an oxygen atom.

R₁₁ is a hydrogen or oxygen atom, two hydrogen atoms, or α- orβ-hydroxyl group or trimethylsilyl ether thereof which makes the C-ring

(a) Δ⁹(11) when R₁₁ is a hydrogen atom,

(b) 9β,11β-epoxide when R₉ and R₁₁ taken together are an oxygen atom andbetween C₁₁ and R₁₁ is a single bond, and

(c) a ketone when R₁₁ is an oxygen atom and between C₁₁ and R₁₁ is adouble bond.

R₂₀ is alkyl of 1 thru 4 carbon atoms or phenyl, the R₂₀ 's can be thesame or different.

R₂₁ is a hydrogen atom, --CO--R₂₁ ' or --Si(R₁₂₁)₃.

R₂₁ ' is alkyl of 1 thru 4 carbon atoms or phenyl.

R₁₂₁ is alkyl of 1 thru 4 carbon atoms or phenyl, the R₁₂₁ 's can be thesame or different.

˜ indicates that the attached group can be in either the α or βconfiguration.

is a single or double bond.

When the term "alkyl of ₋₋ through ₋₋ carbon atoms" is used, it meansand includes isomers thereof where such exist.

X is a hydrogen atom or nothing; when X is nothing the at C₃ is a doublebond and when X is a hydrogen atom the at C₃ is a single bond.

M is a lithium or magnesium ion.

Q is a chlorine, bromine or iodine atom.

E is a chlorine, bromine or iodine atom or --NRαRβ.

Rα is alkyl of 1 thru 5 carbon atoms or phenyl and may be connected orcyclized with Rβ in a ring with or without an oxygen or additionalnitrogen atom.

Rβ is alkyl of 1 thru 5 carbon atoms or phenyl and may be connected orcyclized with Ro in a ring with or without an oxygen or additionalnitrogen atom.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

EXAMPLE 120,21-Dihydroxy-16α-methylpregna-1,4,9(11),17(20)-tetraen-3-one20-trimethyl silyl ether 21-acetate (IIB)

Methyl magnesium chloride in THF (2M, 4.5 ml) is added over a period of2.5 hr to a mixture of 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione21-acetate (IB. U.S. Pat. No. 4,031,080, 2.0 g), THF (27 ml) and cupricacetate monohydrate (60 mg) previously cooled to -52°. The reactiontemperature is kept at less than -40° during the Grignard addition.Following the Grignard addition, TLC indicated no starting material isleft and the reaction mixture is quenched with trimethylsilyl chloride(1.1 ml). The reaction temperature is then slowly permitted to rise to4° over a period of 3 hr at which time TLC indicated the reaction iscomplete. Toluene (15 ml) is added and the THF removed under reducedpressure maintaining the reaction medium at 10°-15°. The reactionmixture is first extracted with a pH 7 buffer, then 4 times with buffer(1 ml) and water (9 ml) and lastly with water. The layers are separatedand the organic layer is dried over sodium sulfate at less than 0° for48 hr. The toluene solution is divided into 35 two-ml portions, one ofwhich is concentrated under reduced pressure to give the title compound.

EXAMPLE 2 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione21-acetate (VB)

m-Chloroperbenzoic acid (0.556 g) is added dropwise to20,21-dihydroxy-16α-methylpregna-1,4,9(11),17(20)-tetraen-3-one20-trimethylsilyl ether 21-acetate (IIB, Example 1, one 35 ml aliquot)over about a 3 hr period keeping the bath temperature in the range ofabout -9° to about 0°. The reaction is quenched with sodium bisulfite(1M. 2.8 ml). Water is added and the phases are separated. The organicphase is washed with water. buffer and water, dried over sodium sulfateand concentrated to a solid. The solid is dissolved in ethylacetate/hexane (5 ml) and crystals formed overnight. The filtrate isconcentrated to a solid which is dissolved in methanol and cooled to 0°.The mixture is filtered, and the crystals washed with cold methanol.

TLC shows some 21-hydroxy compound (V) is present. Acetic anhydride (0.1ml) snd pyridine (0.4 ml) is added and the mixture stirred overnight.The mixture is worked up as is well known to those skilled in the art togive a solid which is crystallized from 40% aqueous methanol to give thetitle compound.

EXAMPLE 39β,11β-Epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione21-acetate (VB)

A mixture of 9β,11β-epoxy-21-hydroxypregna-1,4,16-triene-3,20-dione21-acetate (IB, Example 7, 3.824 g) and cupric acetate monohydrate (200mg) and anhydrous THF (70 ml) at -15° is treated with methyl magnesiumchloride (2.2M, 8.2 ml) added dropwise over 1 hour. After 10 minutes ofstirring at -15° trimethylchlorosilane (1.64 ml) is added. The mixtureis immediately warmed to 20°, stirred for 1 hour at which time TLC showsenol ether (II) formation to be complete. The mixture is added totoluene (100 ml) and this is washed with monobasic phosphate buffer (pH4.25, 50 ml). The organic layer is separated and washed with water (2×50ml) and each aqueous layer is back-extracted with toluene (15 ml). Theorganic phases are combined and concentrated at 55° under reducedpressure to a residue.

Toluene (30 ml) at 0° is added and the mixture treated with peroxyaceticacid (34.5%. 2.91 ml) containing sodium acetate (164 mg). The stirredmixture is warmed to 20° and after 10 minutes TLC indicates theperoxidation is complete. The excess peracid is destroyed by addition ofpowdered sodium thiosulfate (2.5 g) slurried in methanol (10 ml).Hydrochloric acid (6N, 3.0 ml) is added and the hydrolysis is completein about 10 minutes. The mixture is added to toluene (75 ml) and theorganic phase washed with water (2×50 ml), sodium carbonate solution(5%, 40 ml) and finally with water (50 ml). Each aqueous phase isback.extracted sequentially with toluene (20 ml). The organic phases arecombined and concentrated under reduced pressure to a crystallineresidue which is dissolved in hot ethyl acetate and filtered to removetraces of inorganics. Ethyl acetate (about 5 ml) is used for rinse. Thecombined volumes of the filtrate and rinse are reduced to about 10 ml.The solids formed and after about 1 hour hexane (4 ml) is added. Afterstanding at 30°-40° for 2 hours the slurry is cooled to 20°, and thesolids collected by vacuum filtration. The solids are washed with coldethyl acetate:hexane, 1:1 (3 ml), and dried under reduced pressure at50°-60° for 3 hours to give the title compound mp 180°-186° withsoftening at about 135°; NMR (CDCl₃) 0.89, 0.92, 1.43, 3.18 and 4.83 δ.

EXAMPLE 4 9β,11β-Epoxy-6α-fluoro-17α,21-dihydroxy-16 α-methylpregna-1,4-diene-3,20-dione (VB)

A mixture of 9β,11β-epoxy-6α-fluoro-21-hydroxy-1.4,16-triene-3,20-dione21-acetate (IB, U.S. Pat. No. 3,210,341, 8.009 g) cupric acetatemonohydrate (400 mg) and tri-n-butyl phosphine (1 ml) in anhydrous THF(120 ml) at -11° is treated with methyl magnesium chloride (1.95M, 26 5ml) added dropwise over 1 hour. Trimethyl chlorosilane (4 ml) at -8° isthen added. The mixture is immediately allowed to warm to 14° and after20 minutes TLC indicates the reaction is complete. The mixture is addedto ethyl acetate (300 ml) and washed with ammonium hydroxide:saturatedammonium chloride 1:1 (2×75 ml). Each aqueous extract is sequentiallywashed with the same portion of ethyl acetate (210 ml). The combinedorganic phases are then concentrated at 45° under reduced pressure to anoil. The oil is taken up in methylene chloride (120 ml) at -10° andtreated with m-chloroperoxybenzoic acid (85%, 6.092 g) and after 1.5hours TLC indicates the epoxidation is complete. The mixture is vacuumdistilled to replace the solvent with methanol (100 ml) and then themixture is treated with saturated sodium carbonate (20 ml). Afterstirring 16 hours at 20°-25° and 5.25 hours at 55° TLC showed thehydrolysis is complete After cooling to 20°-25° water (100 ml) is addedand the pH adjusted to 7.5 using acetic acid (0.2 ml). Water (160 ml) isthen added portion-wise at 5°. The solids that formed are collected byfiltration, washed with 0° methanol in water (25:75, 50 ml) and driedunder reduced pressure at about 84° over 16 hours to give the titlecompound, mp 241°-241.5°; [α]D²⁵ =+45.7° (DMSO); UV λ_(max) =245 nm(ε=15.300); NMR (CDCl₃ /DMSO-d₆) 0.82, 0.82, 1.40, 3.30, 4.30 and 5.52δ.

EXAMPLE 5 17α,21-Dihydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione21-acetate (VA)

Methyl magnesium chloride in THF (2M, 6 2 ml) is added to a mixture of21-hydroxypregna-4,9(11)-16-triene-3,20-dione 21-acetate (IA, U.S. Pat.No. 4,216,159, 3.68 g) and cupric acetate monohydrate (200 mg) in dryTHF (100 ml) at -50° over a period of 17 minutes. The mixture is stirredat -45° to -50° for 20 minutes and then treated withtrimethylchlorosilane (1.9 ml) and allowed to warm to 20°-25°. After 1.5hours at 20°-25° TLC indicates the enol silyl ether formation iscomplete. The reaction mixture is added to ethyl acetate (150 ml) andthis mixture is washed with cold sulfuric acid (5%, 200 ml), the layersare separated. the aqueous layer is back-extracted with ethyl acetate(25 ml). The original organic layer is washed with cold water (2×150 ml)which in turn was back-extracted with additional ethyl acetate. Theorganic layers phases are combined and concentrated under reducedpressure to about 100 ml.

m-Chloroperoxybenzoic acid (85%, 1.72 g) is added and the mixturestirred 1 hour at -15° following which another 300 mg of peracid isadded and the mixture stirred at 20° overnight. The excess peracid isdestroyed by treatment with sodium bisulfite solution (10%, 20 ml). Themixture is stirred for 20 minutes and then diluted with toluene (200ml). The mixture is then washed with sulfuric acid (5%, 100 ml) andwater (2×100 ml). After concentration to dryness under reduced pressurethe residue is dissolved in methanol (100 ml) and treated withhydrochloric acid (3N, 0.5 ml). The mixture is again concentrated to ahigher boiling residue which is taken up in toluene (200 ml). Thismixture is washed with saturated sodium carbonate (100 ml) to remove them-chlorobenzoic acid. Finally the organic layers are washed with water(2×100 ml) and concentrated as above. The residue dissolved in hotmethanol (20 ml) for crystallization. After cooling to 0° for severalhours a solid is obtained which is collected by vacuum filtration. Theproduct is washed with cold methanol and dried at 20° to give the titlecompound; NMR 0.73, 0.93, 1.33 and 4.98 δ.

EXAMPLE 6 9β,11β-Epoxy-21-hydroxypregna-4,16-diene-3,20-dione 21-acetate(IA)

Following the general procedure of U.S. Pat. No. 3,876,633 and makingnon-critical variations, but starting with21-hydroxypregna-4,9(11),16triene-3,20-dione 21-acetate (U.S. Pat. No.2,773,080), the title compound is obtained, mp 129°-130.5°.

EXAMPLE 7 9β,11β-Epoxy-21-hydroxypregna-1,4,16-triene-3,20-dione21-acetate (IB)

Following the general procedure of U.S. Pat. No. 3,876,633 and makingnon-critical variations, but starting with21-hydroxypregna-1,4,9(11).16-tetraene-3,20-dione 21-acetate (U.S. Pat.No. 2,864,834) the title compound is obtained, mp 163.5°-165°.

EXAMPLE 89β,11β-Epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione (VB)

A mixture of 9β,11β-epoxy-21-hydroxypregna-1,4,16-triene-3,20-dione21-acetate (IB, Example 7, 7.650 g) and cupric acetate monohydrate (400mg) in dry THF (130 ml) is stirred under nitrogen. The temperature isadjusted to -20° and 1,1,3,3-tetramethylurea (5.0 ml) is added. Methylmagnesium chloride (2M, 16.6 ml) is added dropwise over 50 min at -17°to -19° TLC indicates the Grignard reaction is complete. The mixturs isstirred for 40 min at -19°, following which the magnesium enolate isquenched with trimethylchlorosilane (3.28 ml). The temperature rises to25° during the 1 hr stir period. TLC shows this reaction is complete.The mixture is added to toluene (150 ml) and monobasic potassiumphosphate buffer (pH 4.3, 10%. 50 ml). The aqueous layer is extractedwith toluene (25 ml) and then is discarded. The two organic layers arewashed sequentially with water (2×50 ml), then combined and concentratedto a high boiling residue.

The residue containing the Δ¹⁷(20) -20-enol silane is dissolved intoluene (60 ml). After cooling to -5°, 5.9 ml of 4.4M peroxyacetic acidcontaining sodium acetate (91 mg) is added and the mixture stirred for80 min. TLC shows the epoxidation is complete. The excess peracid isdestroyed with aqueous sodium bisulfite (1.5M, 10 ml) at about 0°. Afterstirring 5 min the mixture is added to toluene (40 ml) and water (55ml). The layers are separated and the aqueous phase is extracted withtoluene (20 ml) and then discarded. The two organic layers are washedsequentially with saturated sodium bicarbonate (20 ml) and water (35ml). The combined organic layers are filtered thru cotton andconcentrated to a high boiling residue PG,16 of the 17α,20-epoxide.

The epoxide is taken up in methanol (60 ml) and treated with p-TSA (5mg) at 21°. After 6 min TLC indicates the epoxide is opened and the16α-methyl corticoid has formed (as the 21-acetate). A saturated sodiumcarbonate solution (1.9 ml) is added and the slurry stirred at 55° for45 min. TLC indicates the hydrolysis is complete. Water (30 ml) is addedand the slurry is stored at 0° overnight. The solids are collected byfiltration, washed with methanol/water (1/1) and dried under reducedpressure at 70° for 4.5 hr to give the title compound, mp 238°-239.5°.

EXAMPLE 99β,11β-Epoxy-20,21-dihydroxy-16α-methylpregna-1,4,17(20)-trien-3-one-20-trimethylsilylether 21-acetate (IIB)

Following the general procedure of Example 1 and making non-criticalvariations but starting with9β,11β-epoxy-21-hydroxy-1,4,16-triene-3,20-dione 21-acetate (IB, Example7) the title compound is obtained.

EXAMPLE 10 9α-Fluoro-11β,21-dihydroxypregna-1,4,16-triene-3,20-dione21-acetate (IB)

9β,11β-Epoxy-21-hydroxypregna-1,4,16-triene-3,20-dione 21-acetate (IB,Example 7, 15.3 g) is added to a stirred mixture of aqueous hydrogenfluoride (72%, 55 ml) and methylene chloride (15 ml) at -25° in a 200 mlmonel reactor fitted with a mechanical agitator. About 30 ml ofmethylene chloride is used as a rinse. The mixture is stirred at -22°for 2.5 hr and then at -4° to -11° for 4.0 hr. The mixture is treatedwith THF (35 ml) at -10° and then quenched carefully by slow addition ofa mixture of THF (60 ml), aqueous potassium carbonate (47%, 202 ml) andwater (100 ml). After stirring 20 min the mixture is added to toluene(400 ml) and water (400 ml). The phases are separated and the organiclayer is washed with water (3×150 ml), dried by filtration thru cottonand concentrated to about 150 ml. Methylene chloride (about 150 ml) andmagnesol (0.90 g) is added to the mixture. After 15 min the magnesol isremoved by filtration. The filtrate is again concentrated to 150 ml andthen cooled to 0°. Solids form after stirring at 0° for 3 hr and theproduct is collected by filtration. The solids are washed with toluene(2×25 ml) snd dried at 60° for 3 hr under vacuum to give the titlecompound, mp=223°-225°; NMR (CDCl₃) 1.27, 1.59, 4.29, 4.93 and 6.77 δ.

EXAMPLE 119α-Fluoro-11β,20,21-trihydroxy-16α-methylpregna-1,4,17-(20)-trien-3-one11,20-bis(trimethylsilyl)ether 21-acetate (IIB)

A solution of copper (II) propionate (151 mg) in dry THF (60 ml) iscooled to -30° and then treated with methyl magnesium chloride (2M,about 1 ml) in order to reduce the copper to copper (I).9α-Fluoro-11β,21-dihydroxypregna-1,4,16-triene-3,20-dione 21-acetate(IB, Example 10, 2.025 g) is added to the copper mixture. Thetemperature is adjusted to -33° and the above Grignard reagent (3.0 ml)is added. A slurry forms which is dissolved when treated withtrimethylsilyl chloride (1.50 ml). After stirring 1 hr at -40° another7.4 ml of the Grignard reagent is added portionwise over 50 min. Themixture is stirred another 2 hr and the temperature is allowed to riseto -26°. Then trimethylsilyl chloride (2.0 ml) is added over 1.25 hr at-15°. TLC indicates formation of the Δ¹⁷(20) -enol ether is not completeafter another 0.5 hr at -15°. Grignard reagent (3.0 ml) is added at-35°. After 20 min the mixture is added to toluene (150 ml). Thismixture is washed with 150 ml of water containing 20 ml of 5% phosphatebuffer (pH 6.5). The phases are separated and the organic layer iswashed with water (2×75 ml) and then dried by filtration thru cotton togive the title compound in solution.

EXAMPLE 1217α,20-Epoxy-9α-fluoro-11β,20,2-trihydroxy-16α-methylpregna-1,4-dien-3-one11,20-bis(trimethylsilyl)ether 21-acetate (IIIB)

The above filtrate (Example 11) is concentrated to about 50 ml and aftercooling this mixture to -17° peroxyacetic acid (4.44M, 3.37 ml)containing sodium acetate (67 mg) is added. The mixture is stirred for 4hr whils the temperature is allowed to rise to 7°. The mixture isdiluted with toluene and then washed with water (75 ml). dilute sodiumsulfite and finally with water (75 ml). Each aqueous wash isback-extracted with toluene (50 ml). The organicphases are combined, andconcentrated under vacuum distillation to give a higher boiling residueof crude 17(20)-epoxide-20-trimethylsilyl ether (III).

EXAMPLE 139α-Fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione21-acetate (VB)

The residue (Example 12) is dissolved in methanol (30 ml) and allowed tostand at room temperature. After 0.75 hr the mixture is concentrated to15 ml and water (10 ml) is added. The mixture is filtered to removetraces of insoluble material. The filtrate is diluted with more waterand a waxy solid is collected by decantation. The solid is dried andthen recrystallized from acetone/hexane (1/2, 35 ml). The solids arecollected by filtration. washed with acetone. hexane (1/2, 5 ml) anddried at room temperature to give the title compound. A pure sample ofthe title compound is obtained by column chromatography followed bycrystallization from acetone/hexane (1/1). mp=227°229°; NMR (CDCl₃)0.89, 1.03, 1.57, 4.29 and 4.93 δ.

EXAMPLE 1417α,20-Epoxy-20,21-dihydroxy-16α-methylpregna-1,4,9-(11)trien-3-one20-trimethylsilyl ether 21-acetate (IIIB)

Following the general procedure of Example 12 and making non-criticalvariations, but starting with20,21-dihydroxy-16α-methylpregna-1,4,9(11),17(20)-tetraen-3-one20-trimethylsilyl ether 21-acetate (IIB, Example 1) the title compoundis obtained.

EXAMPLE 159β,11β,17α,20-Diepoxy-20,21-dihydroxy-16α-methylpregna-1,4-dien-3-one20-trimethylsilyl ether 21-acetate (IIIB)

Following the general procedure of Example 12 and making non-criticalvariations, but starting with9β.11β-epoxy-20,21-dihydroxy-16α-methylpregna-1,4,17(20) trien-3-one20-trimethylsilyl ether 21-acetate (IIB, Example 9) the title compoundis obtained.

EXAMPLE 169β,11β-Epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione21-acetate (VB)

A mixture of copper (II) propionate (802 mg) in THF (90 ml) andtetramethylurea (5 ml) are cooled to -25° under nitrogen and treatedwith about 3 ml of methyl magnesium chloride (2M) in order to convertthe blue copper (II) to the yellow.green copper (I) species. Thenmethylene chloride (90 ml), trimethylsilyl chloride (6.56 ml) and9β,11β-epoxy-21-hydroxypregna-1,4,16-triene-3,20-dione 21-acetate (IB,Example 7, 15.30 g) are added and the temperature is lowered to -33°. Atotal of 28 ml of the above Grignard reagent is added to the slurry overa 2.0 hr period. The temperature is maintained at in the range of -33°to -38° during this time. When TLC indicates the reaction to the Δ¹⁷(20)-corticoid silyl ether (II) is complete, the mixture is treated at -10°with ammonium chloride (0.5M, 200 ml). The layers are separated and theorganic layer is washed with water (200 ml). The separate aqueous layersare extracted with methylene chloride (2×50 ml) The organic extracts arecombined and concentrated to give the corresponding Δ¹⁷(22) -corticoidsilyl ether.

This material is dissolved in toluene (100 ml). Sodium acetate (1.0 g)followed by peroxyacetic acid (34%, 11.8 ml) are added at -16°. Themixture is stirred at -16° to 10° over 19 hr following which the excessperacid si quenched with sodium bisulfite (1M). Water (100 ml) is addedand the layers are separated. The aqueous layer is extracted withtolusne (75 ml). The organic layers are washed sequentially with water(2×75 ml) and then combined filtered thru cotton and concentrated. Theconcentrate is dissolved in methanol and reconcentrated to remove allthe toluene and give the correponding 17α,20-epoxide.

The 17α,20-epoxide is dissolved in methylene chloride (40 ml) andmethanol (70 ml) under nitrogen. The temperature is adjusted to 40° anda solution of potassium bicarbonate (200 mg) and potassium carbonate(200 mg) in water (5 ml) is added. This mixture is stirred at reflux(about 42°). After 75 min, TLC indicates both the C₂₀ trimethylsilyl andC₂₁ acetate groups have been removed. The reaction is stopped byaddition of acetic acid (0.6 ml) and the mixture concentrated atordinary pressure to about 50 ml. The resulting slurry is cooled toabout 0° and the solids are collected washed with cold methanol anddried under reduced pressure at 60° to give the title compound, mp 260°with dec. ##STR3##

We claim:
 1. A process for the preparation of a Δ¹⁷(20) -steroid of theformulawhich comprises starting with a 16-unsaturated corticoid of theformula ##STR4## and (1) contacting the 16-unsaturated corticoid (I)with a methylating agent in the presence of a copper catalyst and asilylating agent where R₂₀ is alkyl of 1 thru 4 carbon atoms or phenyl,the R₂₀ 's can be the same or different; R₂₁ is a hydrogen atom,--CO--R₂₁ ' or --Si(R₁₂₁)₃ ; R₂₁ ' is alkyl of 1 thru 4 carbon atoms orphenyl; R₁₂₁ is alkyl of 1 thru 4 carbon atoms or phenyl, the R₁₂₁ 'scan be the same or different.
 2. A process according to claim 1 wherethe methylating agent is selected from the group consisting of compoundsof the formula CH₃ Cu, (CH₃)₂ CuM or CH₃ MgQ where M is a lithium ormagnesium ion and Q is a chlorine, bromine or iodine atom.
 3. A processaccording to claim 2 where the methylating agent is CH₃ MgQ.
 4. Aprocess according to claim 1 where the copper catalyst is a cupric saltselected from the group consisting of cupric acetate, cupric chloride,cupric sulfate, or a cuprous salt selected from the group consisting ofcuprous chloride, cuprous bromide, cuprous iodide and cuprous cyanideand complexes thereof.
 5. A process according to claim 1 where thecopper catalyst is cupric acetate.
 6. A process according to claim 1where the silylating agent is selected from the group consisting of(R₂₀)₃ -Si-E, bistrimethylsilyl acetamide, where E is a chlorine,bromine or iodine atom or --NRαRβ where Rα and Rβ may be the same ordifferent and are alkyl of 1 thru 5 carbon atoms or phenyl and where Rαand Rβ can be connected or cyclized in a ring with or without an oxygenor additional nitrogen atom and where R₂₀ is defined in claim
 1. 7. Aprocess according to claim 1 where the silylating agent istrimethylsilyl chloride.
 8. A process according to claim 1 where the16-unsaturated corticoid (I) is selected from the group consisting of21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate or9β,11β-epoxy-21-hydroxypregna-1,4,16-triene-3,20 dione 21-acetate.
 9. Aprocess according to claim 1 where the 16-unsaturated corticoid (I) isselected from the group consisting of Δ⁴ -3-keto steroids ##STR5## Δ¹. 4-3-keto steroids ##STR6## R₆ is a hydrogen or fluorine atom or methylgroup, R₉ is nothing, a hydrogen, fluorine or oxygen atom which makesthe C-ring(a) Δ⁹(11) when R₉ is nothing and (b) 9β,11β-epoxide when R₉and R₁₁ taken together are an oxygen atom, R₁₁ is a hydrogen or oxygenatom, two hydrogen atoms, or α- or β-hydroxyl group or trimethylsilylether thereof which makes the C-ring(a) Δ⁹(11) when R₁₁ is a hydrogenatom, (b) 9β,11β-epoxide when R₉ and R₁₁ taken together are an oxygenatom and between C₁₁ and R₁₁ is a single bond, and (c) a ketone when R₁₁is an oxygen atom and between C₁₁ and R₁₁ is a double bond, ˜ indicatesthat the attached group can be in either the α or β configuration.